Discovery of Highly Potent and Selective SOS1 Inhibitors for the Treatment of KRAS-Driven Colorectal Cancer

The guanine nucleotide exchange factor SOS1 has emerged as an attractive therapeutic target for various KRAS-driven tumors. Herein, we employed a structure-based drug design strategy to develop a series of novel quinazoline-derived molecules. This effort yielded highly potent and selective SOS1 inhibitors, 78b and 78d, which displayed high SOS1 binding affinity, potently disrupted the SOS1-KRAS^G12C interaction, and inhibited nucleotide exchange in WT and multiple KRAS variants. Moreover, both compounds showed submicromolar 3D-antiproliferative activity across a panel of CRC cells, induced G₁ phase arrest, and suppressed MAPK and PI3K signaling pathways. Furthermore, 78b and 78d demonstrated favorable safety profiles with no observed adverse effects at levels of 500 and 700 mg/kg, respectively. At doses of 60 mg/kg, they achieved significant tumor growth inhibition (75.1% and 86.2%, respectively) in HCT116 xenograft models without significant toxicity. Collectively, this study identifies potent drug candidates with strong pan-KRAS therapeutic efficacy against colorectal cancer.